Virus infection in a genetically predisposed host may induce diabetes mellitus. We have demonstrated in hamsters, mice, and rhesus monkeys that Venezuelan Encephalitis (V.E.) virus replicates in pancreas (hamster) and results in abnormal glucose tolerance and sustained hypoinsulinemia without long term pancreatic pathology. This research plan will extend current studies along two paths. First, the metabolic events associated with VE virus infection will be explored in detail in an in vitro system utilizing isolated perifused hamster islets. In this system, insulin and glucagon secretory capacity and islet cell morphology can be delineated in perifused islets from TC-83 virus infected hamsters. Second, standard virologic methods will be employed to produce a T-83 VE virus variant which is more pancreatropic than the parental TC-83 VE virus. Then, in vivo model systems will be developed to further study VE virus - pancreatic interactions in hamsters. The effects of multiple infections of TC-83 VE and cyclophosphamide treatment in thegenesis of carbohydrate, virologic, pathologic, and immunologic events will be studied. Further, the development of pancreatic islet cell-surface and cytoplasmic antibodies will be assessed in the hamster by immunofluorescent techniques. Finally, insulin and glucagon secretory studies will be performed on TC-83 VE infected hamsters.